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Archives of cardiovascular diseases
Volume 110, n° 12
pages 700-711 (décembre 2017)
Doi : 10.1016/j.acvd.2017.08.002
Received : 5 June 2017 ;  accepted : 16 August 2017
Role of tumour necrosis factor alpha converting enzyme (TACE/ADAM17) and associated proteins in coronary artery disease and cardiac events
Rôle de l’enzyme de conversion TNF (TACE/ADAM17) et des protéines associées dans la maladie coronaire et les événements cardiaques
 

Figure 1




Figure 1 : 

TACE domains. Signal peptide (1-17 aa); pro-domain (18-214 aa) acting as an inactivator and a chaperone domain; extracellular domain (215-671 aa) comprising: 1. A metalloprotease domain/catalytic domain (215-473 aa) responsible for an ectodomain shedding; 2. A disintegrin domain (474-572 aa); 3. An EGF-like/cysteine rich domain (573-671 aa) responsible for substrate recognition and activation; transmembrane domain (672-694 aa) necessary for effective cleavage of substrates; cytoplasmic domain (695-824 aa) binding to many proteins that regulate TACE activity. aa: amino acid; EGF: endothelial growth factor; TACE: tumour necrosis factor alpha converting enzyme.


Figure 2




Figure 2 : 

TACE activation and regulation. 1. Once synthesized, iRhom bind to TACE and promotes maturation, its exit from the endoplasmic reticulum and its migration to the Golgi. 2. TACE prodomain is cleaved by furin in the trans-Golgi network. 3. During maturation, ERK-dependent threonine 735 phosphorylation is necessary for TACE to reach the secretory pathway. 4. TACE is packaged into lipid rafts during its transport and maturation through the Golgi. 5. Most of the active form of TACE is localized in the cellular perinuclear region, with a small amount present in the plasma membrane. 6. TACE has an increased shedding rate when exposed to cell activators, such as phorbol esters, including PMA. Other activators include lipopolysaccharide, which is dependent on ROS and the p38 MAPK pathway. 7. TACE is present in dimers on the cell surface and binds to its inhibitor TIMP3. 8. Activation of the ERK or p38 MAPK pathway transforms TACE from a dimer structure into a monomer structure and releases it from TIMP3. 9. TACE is regulated by FHL2 and SAP97. 10. TACE cleaves transmembrane TNFα and releases soluble TNFα. ER: endoplasmic reticulum; ERK: extracellular signal-regulated kinases; FHL2: four and a half LIM domains 2; LPS: lipopolysaccharide; iRhom2: rhomboid family member 2; MAPK: mitogen-activated protein kinases; PKC: protein kinase C; PMA: phorbol myristate acetate; PTPH1: protein-tyrosine phosphatase; ROS: reactive oxygen species; SAP97: synapse-associated protein 97; sTNFα: soluble TNFα; TACE: tumour necrosis factor alpha converting enzyme; TIMP3: tissue inhibitor of metalloproteinases 3; tmTNFα: transmembrane TNFα; TNFα: tumour necrosis factor alpha.


Figure 3




Figure 3 : 

Possible role of TACE in cardiac events. This diagram shows the different proteins cleaved by TACE that are involved in chronic arterial wall inflammation occurring in atherosclerosis. As an example, TACE cleaves transmembrane TNFα, TNFR1 and TNFR2 releasing their soluble forms, sTNFα, sTNFR1 and sTNFR2, respectively. The transmembrane ectodomain shedding combined with a premature endothelial cell senescence due to TACE, leads to amplification of inflammation as well as reduction in endothelial health. This results in an increased risk of plaque rupture and thrombosis, and an overall increased risk of developing cardiovascular events. sTNFα: soluble tumour necrosis factor alfa; sTNFR1: soluble tumour necrosis factor alfa receptor 1; sTNFR2: soluble tumour necrosis factor alfa receptor 2; TACE: tumour necrosis factor alpha converting enzyme; tmTNFα: transmembrane TNFα; TNFα: tumour necrosis factor alfa; TNFR1: tumour necrosis factor alfa receptor 1; TNFR2: tumour necrosis factor alfa receptor 2.

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